Project Summary Over 100,000 peripheral nerve injuries (PNI) including motor vehicle and combat accidents occur annually in the U.S. and Europe. In addition, PNI accounts for nearly one- fourth of the pediatric nerve damage. Common causes in children include direct trauma related to birth (e.g. brachial plexus), motor vehicle accidents, as well as tumor, vascular, and compression injuries. In the U.S., approximately $150 billion is spent each year as a result of nerve injury, with 87% of these costs due to lost production outside of healthcare system. The majority of patients are left with lifelong disability and functional deficits, creating a major personal and societal burden. The current gold standard is to use a patient's own nerves harvested from one location to treat nerve defects (>10 mm) at injury site. However, the drawbacks are significant including the limited availability of the donor nerve, size of donor nerve, and scarring and complications occurring at the surgical sites. More recently, human neural stem cells (hNSCs) have emerged as a potential treatment for neural recovery. However, there is limited graft survival (5-20%) immediately following transplantation due to acute inflammatory/immune response, neurotrophic factor withdrawal, and oxidative stresses in the complex microenvironment. This subsequently diminishes the therapeutic effectiveness of hNSC therapy. It is crucial to understand how transplanted hNSCs are influenced by their microenvironmental cues to sustain their viability and elicit the desired cellular behaviors to enhance nerve repair. Stem cells interact with their microenvironment through biochemical factors, matrix proteins, and cell-cell interactions. My research focuses on using regenerative strategies to biophysical, biochemical, and bioelectrical microenvironment to further enhance the therapeutic potential and sustain the survival of transplanted hNSCs to repair nerve defects. Specifically, hNSCs will be electrically stimulated and encapsulated in silicon nanopore membrane (SNM) for enhanced therapeutic effectiveness and survival. In addition, physical rehabilitation will be implemented to promote nerve recovery. The goal of this research is to understand biological pathways related to peripheral nerve repair through biochemical modulation, and electrical and physical rehabilitation to enhance the therapeutic potential of hNSCs. By understanding the interplay between stem cells and various forms of rehabilitation strategies (e.g. electrical stimulation, physical exercise), we can investigate new device approaches and identify essential pathways that can translate into better neural recovery and nerve regeneration strategies for PNI in humans.